Van Der Poll Research Articles

Stable learning laws design for long short-term memory identifier for uncertain discrete systems via control Lyapunov functions

This study introduces a method for designing stable learning laws of Long Short-Term Memory (LSTM) networks working as a non-parametric identifier of nonlinear systems with uncertain models. The strategy applies the concept of stability for discrete-time systems in the sense of Lyapunov to prove that origin is a practical stable equilibrium point for the identification error. The laws consider a general class of sigmoidal functions placed at the different gates of a LSTM structure (long and short memory). The design of the learning laws uses a matrix inequality framework to obtain the rate gains associated with the evolution of the weights. Numerical results show the designed learning laws for the non-parametric identifier based on a LSTM approximation tested on two classes of nonlinear systems: the first one describes the ozone-based degradation of organic contaminants, and the second one represents the dynamics of a Van Der Poll oscillator. The LSTM identifier is compared against a classical Lyapunov-based recurrent neural network. This comparison demonstrates how the proposed algorithm approximates the trajectories of both systems with a smaller mean squared error, which serves as an indicator of the benefits obtained with these new learning laws.

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

1374. Integrated Safety Summary of Omadacycline: A Novel Aminomethylcycline Antibiotic

BackgroundOmadacycline (OMC) is a novel aminomethylcycline with activity against Gram-positive, many Gram-negative, anaerobic, and atypical pathogens. It is in clinical development as once-daily oral (PO) and intravenous (IV) monotherapy for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Cumulative safety results from Phase 3 clinical trials are reported.MethodsThis pooled safety analysis is based on 2,150 subjects: OASIS-1 (N = 645), OASIS-2 (N = 735) in ABSSSI; OPTIC (N = 770) in CABP. Comparators were linezolid (LZD) 600 mg IV then PO in ABSSSI (n = 689); moxifloxacin (MOX) 400 mg IV then PO in CABP (n = 388). Safety parameters included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, and electrocardiogram (ECG) findings.ResultsA total of 1,073 subjects received OMC: 705 received OMC IV then PO (ABSSSI, n = 323; CABP, n = 382); 368 received OMC PO only for ABSSSI. Overall, 60.6% were male and 91.6% white; mean age ranges were 44.7–45.1 and 60.9–62.1 years in ABSSSI and CABP studies, respectively. TEAEs were observed in 47.5% (OMC), 41.2% (LZD), and 48.5% (MOX) of subjects, with gastrointestinal events the most common TEAEs. Serious TEAEs were low (3.6% OMC, 1.9% LZD, 6.7% MOX). Nausea (14.9% OMC, 8.7% LZD, 5.4% MOX) and vomiting (8.3% OMC, 3.9% LZD, 1.5% MOX) were the most frequently reported TEAEs. Diarrhea was observed in 2.4% OMC, 2.9% LZD, and 8.0% MOX subjects, with no cases of Clostridium difficile in OMC-treated subjects. Most TEAEs were mild to moderate and did not result in study drug discontinuation (3.1% OMC, 1.5% LZD, 7.0% MOX); 4 OMC, 1 LZD, and 0 MOX subjects discontinued for nausea and vomiting. Frequency of hepatic TEAEs was similar for OMC, LZD, and MOX: 4.3% OMC, 4.1% LZD, and 4.5% MOX subjects had post-baseline ALT >3× upper limit of normal. Vital signs and ECGs had comparable clinically notable values post-baseline in each treatment group. Known tetracycline class adverse events such as fungal infections were similar in all groups.ConclusionPooled analyses demonstrate a favorable OMC safety profile, consistent with its tetracycline heritage. OMC was generally well tolerated in subjects with ABSSSI and CABP, with infrequent treatment discontinuations.Disclosures T. M. File Jr., BioMerieux: Consultant, Consulting fee; Curetis: Consultant, Consulting fee; Melinta Therapeutics: Consultant, Consulting fee; Merck: Consultant, Consulting fee; Motif Bio: Consultant, Consulting fee; Nabriva Therapeutics: Consultant and Investigator, Consulting fee and Research grant; Paratek Pharmaceuticals: Consultant, Consulting fee; Pfizer: Consultant, Consulting fee. T. Van Der Poll, Paratek Pharmaceuticals: Consultant, Consulting fee. P. McGovern, Paratek Pharmaceuticals: Employee, Salary. E. Tzanis, Paratek Pharmaceuticals: Employee, Salary.

Abstract 5135: Sustained and controlled in vivo therapeutic levels of drug payloads in tumors using two separate drug combination platforms: Antibody nanoparticle-drug conjugates and multi-drug nanoparticle-drug conjugates, with the potential for improved drug combinability and anticancer effects

Abstract Our nanoparticle-drug conjugates (NDCs), created at Cerulean Pharma Inc. by conjugating drug payloads to our novel β-cyclodextrin-PEG (CDP) copolymer, are designed to significantly mitigate a payload’s limitations by providing sustained drug delivery to the tumor and superior therapeutic index through controlled release kinetics. Cerulean has two NDCs in the clinic, CRLX101 and CRLX301, evidencing the translatability of our technology. CRLX101 has been dosed in over 400 patients and CRLX301 is in ongoing Phase 2a development. A key and differentiating feature of our NDC Platform is our linker technology, which is tailored for an optimal fit with the conjugation functionality of the API drug payloads (e.g., alcohol, carboxylic acid, amine, amide and urea functionality) and customizable to achieve desired drug release profiles. As an illustration of Cerulean’s ability to expand its NDC platform, we will present the biological and pharmacokinetic (PK) data supporting our drug combination platform of antibody nanoparticle-drug conjugates (ANDCs) and multi-drug nanoparticle-drug conjugates (mNDCs). ANDCs combine potentially any NDC with any conjugatable biologic to generate an ANDC with ultra-high drug-antibody ratios (DARs). Using our established NDC linker technology, we generated Herceptin-camptothecin ANDCs with DARs as high as 500, orders of magnitude higher than ADCs, and no more than 5-fold loss in binding (greater than 90% binding up to 300 DAR) compared to native Herceptin in our solution-based HER2 antigen binding assay. In addition, we provide evidence experimentally that rhodamine-labeled ANDCs penetrate and internalize in HER2+ tumor cells. The ANDCs demonstrate tunable in vitro release kinetics and long in vivo half lives in mouse PK studies, including sustained levels of released drug in tumors (greater than 300h) using an ANDC (average DAR 201) delivering an 8 mg/kg camptothecin dose. The observed mouse MTD for the ANDC was at least 3x higher than that of the corresponding NDC. The mNDCs take advantage of our existing NDC linker platform technology to conjugate diverse drug combos including DNA damaging agents (DDA) + DNA damage repair agents (DDR). We generated our POC camptothecin-olaparib mNDCs spanning a range of drug combination ratios (from 1:1 to 1:20) and all demonstrated distinguishable and tunable in vitro release rates. PK study of a 1:1 camptothecin-olaparib mNDC (~8mg/kg each drug) demonstrated very low clearance and sustained levels of released drug in tumor (greater than 72h). Our drug combination platforms, ANDCs and mNDCs, allow delivery of therapeutic agents to their respective biological targets at clinically-relevant doses, greatly increasing the diversity of drug combination possibilities. Note: This abstract was not presented at the meeting. Citation Format: Chester A. Metcalf, Derek van der Poll, Liang Zhao, Roy I. Case, Doug Lazarus, Donna Brown, Tiffany Halo, Lata Jayaraman, Christian Peters, Ellen Rohde, Scott Eliasof. Sustained and controlled in vivo therapeutic levels of drug payloads in tumors using two separate drug combination platforms: Antibody nanoparticle-drug conjugates and multi-drug nanoparticle-drug conjugates, with the potential for improved drug combinability and anticancer effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5135. doi:10.1158/1538-7445.AM2017-5135

Abstract PR10: Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects

Abstract Cerulean Pharma Inc.'s Dynamic Tumor Targeting™ Platform creates nanoparticle-drug conjugates (NDCs) designed to significantly mitigate a payload's limitations by providing sustained drug delivery to the tumor and superior therapeutic index through controlled release kinetics. By conjugating drug payloads to our novel β-cyclodextrin-PEG copolymer through linker strategies that allow modulation of release and pharmacokinetics (PK), we provide advantages over entrapped nanoparticle strategies, e.g., polymeric nanoparticles and liposomes. Cerulean has two NDCs in the clinic, CRLX101 and CRLX301, evidencing the translatability of our technology. CRLX101 has been dosed in over 350 patients and CRLX301 is in an ongoing Phase 1/2a trial. Our Dynamic Tumor Targeting Platform is applicable to a diverse range of drug payload possibilities, including small molecules with a host of physiochemical properties, i.e., hydrophobic and hydrophilic payloads, and functional groups with chemical handles for conjugation. To illustrate the capabilities of our platform we will present the biological impact of a series of cabazitaxel-containing NDCs with linkers encompassing a diversity of in vitro release rates. In vivo PK studies showed high and sustained levels of released drug in tumor tissues (>168 hrs), and in vivo mouse tumor model studies demonstrated vastly improved efficacy, i.e., tumor regression and significant tumor growth delay, and survival over separately dosed cabazitaxel including efficacy in a taxane-resistant tumor model. Cerulean continues to expand its platform through the development of new and emerging capabilities to treat patients living with cancer. In this regard, we also will address the future evolution of NDCs, including the conjugation of multiple payloads to a single NDC and the development of antibody-conjugated NDCs. This abstract is also being presented as Poster B43. Citation Format: Chester Metcalf, III, Derek van der Poll, Liang Zhao, Tiffany Halo, Doug Lazarus, Adam Stockmann, Christian Peters, Donna Brown, Roy Case, Ellen Rohde, Lata Jayaraman, Hongwei Wang, Tiffany Crowell, Adrian Senderowicz, Scott Eliasof. Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR10.

Detection of Pathogens in Blood for Diagnosis of Sepsis and Beyond

Detection of Pathogens in Blood for Diagnosis of Sepsis and Beyond

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality

The striking coagulopathy in patients with severe sepsis and the increasing insight into the intricate link between inflammation and coagulation has been an inspiration for many researchers and pharmaceutical companies to explore potential therapeutic interventions for severe sepsis [1]. Indeed, in view of the high incidence of severe sepsis and sepsis mortality ranging from 20 to 50%, there is a urgent need for better treatment options [2]. As dysfunctional physiological anticoagulant regulators, such as antithrombin, activated protein C, and tissue factor pathway inhibitor, were shown to be key players in the sepsis-associated activation of coagulation, and animal studies supported the hypothesis that restoration of these pathways resulted in attenuation of coagulopathy and organ dysfunction and reduced mortality, large clinical studies were performed to establish the beneficial effect of these interventions in patients with severe sepsis [2-5]. Although some of these studies demonstrated some advantage in subgroups of patients with most extreme coagulopathies an overall reduction in mortality was not confirmed. This article is protected by copyright. All rights reserved

Association between neutrophil to lymphocyte ratio and atrial fibrillation

Neutrophil to lymphocyte ratio (NLR) is a ratio of subtypes of leukocyte and has been attracting attention as a significant biomarker of systemic inflammation [ [1] de Jager C.P. van Wijk P.T. Mathoera R.B. de Jongh-Leuvenink J. van der Poll T. Wever P.C. Lymphocytopenia and neutrophil–lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit. Care. 2010; 14 (England): R192 Crossref PubMed Scopus (369) Google Scholar ]. Inflammation has a significant role in atherosclerosis [ [2] Ross R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 1999; 340: 115 Crossref PubMed Scopus (19066) Google Scholar ]. NLR has been shown to be related to adverse outcomes in patients with coronary heart disease (CHD) [ 3 Nunez J. Nunez E. Bodi V. Sanchis J. Minana G. Mainar L. et al. Usefulness of the neutrophil to lymphocyte ratio in predicting long-term mortality in ST segment elevation myocardial infarction. Am. J. Cardiol. 2008; 101 (United States): 747-752 Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar , 4 Azab B. Zaher M. Weiserbs K.F. Torbey E. Lacossiere K. Gaddam S. et al. Usefulness of neutrophil to lymphocyte ratio in predicting short- and long-term mortality after non-ST-elevation myocardial infarction. Am. J. Cardiol. 2010; 106 (United States): 470-476 Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar , 5 Tamhane U.U. Aneja S. Montgomery D. Rogers E.K. Eagle K.A. Gurm H.S. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am. J. Cardiol. 2008; 102 (United States): 653-657 Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar , 6 Papa A. Emdin M. Passino C. Michelassi C. Battaglia D. Cocci F. Predictive value of elevated neutrophil–lymphocyte ratio on cardiac mortality in patients with stable coronary artery disease. Clin. Chim. Acta. 2008; 395 (Netherlands): 27-31 Crossref PubMed Scopus (272) Google Scholar , 7 Kaya M.G. Akpek M. Lam Y.Y. Yarlioglues M. Celik T. Gunebakmaz O. et al. Prognostic value of neutrophil/lymphocyte ratio in patients with ST-elevated myocardial infarction undergoing primary coronary intervention: a prospective, multicenter study. Int. J. Cardiol. 2013; 168 (Netherlands): 1154-1159 Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar , 8 Balta S. Demirkol S. Aparci M. Celik T. Ozturk C. The neutrophil lymphocyte ratio in coronary heart disease. Int. J. Cardiol. 2014; 176 (Netherlands): 267 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar , 9 Shah N. Parikh V. Patel N. Patel N. Badheka A. Deshmukh A. et al. Neutrophil lymphocyte ratio significantly improves the Framingham risk score in prediction of coronary heart disease mortality: insights from the National Health and Nutrition Examination Survey-III. Int. J. Cardiol. 2014; 171: 390-397 Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar ] and can independently predict mortality of CHD in an asymptomatic population [ [9] Shah N. Parikh V. Patel N. Patel N. Badheka A. Deshmukh A. et al. Neutrophil lymphocyte ratio significantly improves the Framingham risk score in prediction of coronary heart disease mortality: insights from the National Health and Nutrition Examination Survey-III. Int. J. Cardiol. 2014; 171: 390-397 Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar ]. Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and increases the risk of stroke and death. Inflammation, which is related to the initiation and maintenance of AF, plays a key role in AF [ 10 Aviles R.J. Martin D.O. Apperson-Hansen C. Houghtaling P.L. Rautaharju P. Kronmal R.A. et al. Inflammation as a risk factor for atrial fibrillation. Circulation. 2003; 108: 3006-3010 Crossref PubMed Scopus (1131) Google Scholar , 11 Aronson D. Boulos M. Suleiman A. Bidoosi S. Agmon Y. Kapeliovich M. et al. Relation of C-reactive protein and new-onset atrial fibrillation in patients with acute myocardial infarction. Am. J. Cardiol. 2007; 100 (United States): 753-757 Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar , 12 Chung M.K. Martin D.O. Sprecher D. Wazni O. Kanderian A. Carnes C.A. et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001; 104 (United States): 2886-2891 Crossref PubMed Scopus (1130) Google Scholar ]. However, little is known about the association between NLR levels and AF.

50th Anniversary Congress of the Dutch Society of Immunology

50^th Anniversary Congress of the Dutch Society of Immunology

OP0114 Interim Safety and Efficacy Results of Patients with Cryopyrin-Associated Periodic Syndrome Participating in the β-Confident Registry

BackgroundCryopyrin-associated periodic syndrome (CAPS) is a continuum of rare hereditary disorders that includes three phenotypes, in the order of severity: familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic...

An acute phase protein ready to go therapeutic for sepsis

The so-called Acute Phase Response (APR) begins between 12 and 48 h after the initiation of inflammation. This conserved response mainly involves the production of a set of Acute Phase Proteins (APPs) and the downregulation of other proteins (negative APPs) by hepatocytes. Although the precise identity of the APPs may differ between species, some APPs are common in all mammals.

THU0392 Beta-confident-registry: Efficacy and safety of canakinumab in cryopyrin associated periodic syndrome - 18 month follow-up

BackgroundCanakinumab (CAN, Ilaris®), a fully human anti-IL-1β monoclonal antibody, selectively inhibits IL-1β and has been approved for the treatment of cryopyrin-associated periodic syndrome (CAPS), an extremely rare inherited inflammatory disorder.ObjectivesThe...

THU0464 Safety Results from the B-Confident Registry in Canakinumab-Treated Patients with Cryopyrin-Associated Periodic Syndrome (CAPS)

BackgroundCanakinumab (CAN), a fully human, selective, anti-interleukin (IL)-1β monoclonal antibody, is approved for the treatment of CAPS, an extremely rare autoinflammatory disorder associated with overproduction of IL-1β, including the subtypes...

Deficiency of Growth Factor Midkine Exacerbates Necrotizing Glomerular Injuries in Progressive Glomerulonephritis

Inflammatory cell infiltration and fibrin deposition play important roles in the development of crescentic glomerulonephritis (GN). In particular, activation of coagulation is an indispensable factor in crescent formation. However, the mechanisms underlying the pathogenesis of crescent formation have not been completely elucidated. We identified the growth factor midkine (MK) as a novel key molecule in the progression of crescentic GN induced by anti-glomerular basement membrane antibody. Despite the lack of significant differences in autologous and heterologous reactions, MK-deficient (Mdk(-/-)) mice unexpectedly showed a greater number of necrotizing glomerular injuries than wild-type (Mdk(+/+)) mice. Likewise, more tubulointerstitial damage was observed in Mdk(-/-) mice, and this damage positively correlated with glomerular injury. Plasminogen activator inhibitor (PAI)-1 was strongly induced in the injured glomerulus of Mdk(-/-) mice, particularly in crescents and endothelial cells. This enhanced PAI-1 production was associated with an increase in inflammatory cell infiltration and matrix deposition in the glomerulus and the interstitium of Mdk(-/-) mice. In line with these invivo data, primary cultured endothelial cells derived from Mdk(-/-) mice exhibited higher PAI-1 mRNA expression on fibrin challenge and less fibrinolysis than Mdk(+/+) mice. In contrast, the expression of plasminogen activators was not affected. Our combined data suggest that MK leads to a blockade of PAI-1, which is closely associated with the suppression of crescentic GN.

Combination Antibiotics and Outcome of Life-Threatening Bacterial Infections and Septic Shock

Untreated septic shock is usually fatal within 24 to 36 hours. Clinical trials with anti-inflammatory agents in patients with sepsis are based on the assumption that the pathogenesis of sepsis is primarily driven by excessive proinflammatory activity of the cytokine network even though the triggering infection may have been eliminated by appropriate antimicrobial therapy [van der Poll T, van Deventer SJ. Infect Dis Clin North Am 1999]. It has been suggested that the failure of these trials to show clinical benefit, in conjunction with recent experimental data, raises doubt about the validity of this assumption.

Similar virologic response after initiation of triple-class antiretroviral therapy in primary and chronic HIV infection

Similar virologic response after initiation of triple-class antiretroviral therapy in primary and chronic HIV infection

Erratum to: Kinase Activity Profiling of Gram-Negative Pneumonia

In the margin of page 742 of the following article, a red arrow was left from the production process; it has no meaning with respect to the figure or figure legend: Arie J Hoogendijk, Sander H Diks, Maikel P Peppelenbosch, Tom van der Poll, and Catharina W Wieland. Kinase Activity Profiling of Gram-Negative Pneumonia. Mol. Med. 2011;17(7–8):741–7.

Tissue factor pathway inhibitor and bacterial infection

See also van den Boogaard FE, Brands X, Schultz MJ, Levi M, Roelofs JJTH, van 't Veer C, van der Poll T. Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inflammatory and antimicrobial effects in murine pneumococcal pneumonia. This issue, pp 122-32.

Flexibility of the Thrombin-activatable Fibrinolysis Inhibitor Pro-domain Enables Productive Binding of Protein Substrates

We have previously reported that thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits intrinsic proteolytic activity toward large peptides. The structural basis for this observation was clarified by the crystal structures of human and bovine TAFI. These structures evinced a significant rotation of the pro-domain away from the catalytic moiety when compared with other pro-carboxypeptidases, thus enabling access of large peptide substrates to the active site cleft. Here, we further investigated the flexible nature of the pro-domain and demonstrated that TAFI forms productive complexes with protein carboxypeptidase inhibitors from potato, leech, and tick (PCI, LCI, and TCI, respectively). We determined the crystal structure of the bovine TAFI-TCI complex, revealing that the pro-domain was completely displaced from the position observed in the TAFI structure. It protruded into the bulk solvent and was disordered, whereas TCI occupied the position previously held by the pro-domain. The authentic nature of the presently studied TAFI-inhibitor complexes was supported by the trimming of the C-terminal residues from the three inhibitors upon complex formation. This finding suggests that the inhibitors interact with the active site of TAFI in a substrate-like manner. Taken together, these data show for the first time that TAFI is able to form a bona fide complex with protein carboxypeptidase inhibitors. This underlines the unusually flexible nature of the pro-domain and implies a possible mechanism for regulation of TAFI intrinsic proteolytic activity in vivo.